High-dose supplementation with natural α-tocopherol does neither alter the pharmacodynamics of atorvastatin nor its phase I metabolism in guinea pigs

Vitamin E–drug interactions: molecular basis and clinical relevance

“…In LS180 colon cells, neither T nor T 3 (10 mmol/l; 24 h) altered the mRNA expression of CYP3A4 (30) . In agreement with these in vitro findings, the intestinal protein expression of CYP3A4 did not differ between guinea-pigs fed RRR-aT at normal dietary (20 mg/kg diet) or pharmacological doses (250 mg/kg diet) for 6 weeks (37) .…”

“…The hepatic protein expression of CYP3A4 and CYP20A1 and the serum concentrations of the CYP3A4 products of atorvastatin, paraand ortho-hydroxy-atorvastatin were similar in both groups. In agreement with this, the cholesterol-lowering activity of atorvastatin was unaltered by high-dose aT feeding (37) . This is in agreement with studies in human subjects addressing the effects of aT on CYP3A4mediated drug metabolism.…”

The long chain α–tocopherol metabolite α‐13’‐COOH and γ‐tocotrienol induce P‐glycoprotein expression and activity by activation of the pregnane X receptor in the intestinal cell line LS 180

“…Upon loading of the liver with supraphysiological doses of αT, for example via subcutaneous injection, vitamin E side chain degradation capacity may be exceeded, which then results in the accumulation of the precursor of α‐13’‐COOH, 13’‐OH‐α‐tocopherol, as previously reported . The α‐13’‐COOH formed upon exposure to very high doses of αT may thus be the true inducer of PXR and its target genes and may explain why studies using high doses of αT did not find induction of PXR targets whereas studies employing supraphysiological doses did .…”

“…The ability of the intermediate α‐13’‐COOH to induce PXR, while the parent compound is ineffective, may explain differences in the hepatic expression of PXR target genes (such as P‐gp and cytochrome P450 3A4 (CYP3A4)) in response to αT intake reported in the literature. αT did neither alter the pharmacodynamics of atorvastatin or midazolam, nor the activity of CYP3A4 in guinea pigs fed 250 mg αT per kg diet for 6 weeks or humans supplemented with 400 mg αT/d for 8 weeks , respectively. Mice fed a supraphysiological dose of 1000 mg αT/kg diet (corresponding to 7–10 g/d for an average human) for 4 months, on the other hand, presented induced hepatic mRNA expression of Cyp3a11, the murine homologue of CYP3A4 .…”

“…The literature provides evidence for and against effects of vitamin E on the expression and activity of efflux transporters and xenobiotic enzymes via activation of PXR and this has been previously reviewed . In summary high doses of αT in rodents induced mRNA expression of the PXR target genes Cyp3a11and Mdr1a in mice and MDR1 in rats but did not affect CYP3A4 mediated metabolism in humans and guinea pigs .…”